The purpose of these studies is to continue to evaluate the toxic effects of MDMA and METH (Ecstasy) in SOD-Transgenic mice, and p53 knock-out. The subacute and long-term biochemical effects of methamphetamine (METH) were assessed in homozygous and heterozygous transgenic (Tg) mice that carry the complete sequence of the human copper-zinc (CuZn) superoxide dismutase (SOD) gene. METH injections caused marked depletion of dopamine terminals in wild-type mice. However, both heterozygous and homozygous SOD-Tg mice showed protection against the toxic effects of METH with the homozygous animals showing the greatest protection. These data suggest that superoxide radicals are involved in the neurotoxic effects of METH. We also wanted to evaluate the toxic effects of METH in p53 knock out mice. We reasoned that if METH causes neurodegeneration, it might be doing it through activation of cell death related genes. Our observations show that wild-type mice were exquisitely sensitive to the long-term effects of the drug whereas the p53 knockout mice were protected. In addition, METH cased induction of p53 in the striatum of mice. These results indicate that METH is an apogean that affects DA systems in the brain.